Napovedni dejavniki za težke sistemske zaplete med imunoterapijo

Kopač, Peter (author), Košnik, Mitja (mentor), Korošec, Peter (co-mentor)

Uvod: specifična imunoterapija je edini način zdravljenja pacientov, ki so imeli težko anafilaksijo po piku kožekrilca. Med imunoterapijo lahko pride do težkih zapletov, zato jo je pri nekaterih pacientih treba prekiniti. Namen dela: ugotoviti dejavnike, ki napovedujejo težke zaplete med imunoterapijo s strupi kožekrilcev in ugotoviti, ali dodatno zdravljenje z omalizumabom omogoča varno uvedbo imunoterapije pri pacientih s ponavljajočimi se težkimi zapleti med imunoterapijo. Metode: analizirali smo pojavnost in težo sistemskih zapletov med imunoterapijo pri pacientih, pri katerih smo na Univerzitetni kliniki Golnik uvedli imunoterapijo v letih 2005–2016, ter analizirali klinične (starost, spol, teža izvorne reakcije) in imunološke (koncentracija specifičnih IgE proti celotnemu ekstraktu strupa čebele in ose ter proti posameznim rekombinatno pridobljenim alergenom, bazalna triptaza, test aktivacije bazofilcev) dejavnike tveganja za pojav sistemskih zapletov. Paciente, pri katerih smo imunoterapijo prekinili zaradi zapletov, smo zdravili z omalizumabom in ponovno poskušali uvesti imunoterapijo. Rezultati: sistemski zapleti med imunoterapijo se pojavljajo pri 10,8 %, pri 1,3 % pa smo morali imunoterapijo zaradi zapletov prekiniti. Poglavitni dejavnik tveganja za zaplete med imunoterapijo je zdravljenje s strupom čebele: med imunoterapijo s strupom čebele je imelo zaplete 23,1 %, med imunoterapijo s strupom ose pa 1,8 % pacientov (P < 0,0001). Pacienti z zapleti med imunoterapijo s strupom čebele so imeli težjo izvorno reakcijo po piku čebele (P = 0,013). Pacienti, pri katerih smo imunoterapijo s strupom čebele prekinili zaradi zapletov, so imeli višjo bazalno koncentracijo triptaze (5,23 µg/ml) v primerjavi s pacienti z obvladljivimi zapleti (4,29 µg/ml) ter pacienti brez zapletov (4,35 µg/ml) (P ? 0,01). Prav tako so imeli pacienti, pri katerih smo imunoterapijo s strupom čebele prekinili zaradi zapletov, višjo aktivacijo bazofilcev s strupom čebele pri koncentracijo 0,1 µg/ml (79,1 % ) v primerjavi s pacienti brez zapletov (39,0 %) in z blagimi zapleti (62,6 %) (P ? 0,003). Napovedni dejavnik za težke zaplete med imunoterapijo je visoka aktivnost bazofilcev pri stimulaciji z 0,1 µg/ml strupa čebele (OR (95 % CI) 1,041 (1,005–1,073), P=0,0004). Zdravljenje z omalizumabom omogoča varno in uspešno uvedbo imunoterapije pri 9 od 11 pacientov. Pojavnost zapletov med imunoterapijo je bila bistveno manjša, če je bila aktivnost bazofilcev pri stimulaciji z 0,1 µg/ml strupa čebele pod 20 % (P = 0,0004). Zaključek: potrdili smo, da obstajajo napovedni dejavniki za težke sistemske zaplete med imunoterapijo – občutljivost bazofilcev in bazalni nivo serumske triptaze. Zdravljenje z omalizumabom zmanjša občutljivost bazofilcev ter omogoča varno uvedbo imunoterapije pri pacientih, ki so imeli več težkih sistemskih reakcij med imunoterapijo. Dinamika občutljivosti bazofilcev napoveduje tudi klinični uspeh zdravljenja z omalizumabom.

• Language: Slovenian
• Keywords: alergija, strup kožekrilcev, anafilaksija, imunoterapija, omalizumab, bazofilec, mastocit, triptaza, biomarker
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2022
• PID: 20.500.12556/RUL-134433
• COBISS.SI-ID: 93887747
• Publication date in RUL: 14.01.2022

Secondary language

• Language: English
• Title: Predictors of severe adverse events during venom immunotherapy

Abstract

Introduction: Venom immunotherapy (VIT) is the only effective treatment to prevent further systemic reactions in patients with Hymenoptera venom allergy. However, during immunotherapy patients can develop systemic adverse events (SAEs) and in some cases, VIT has to be stopped due to recurrent and severe SAEs (VIT failure due to SAEs). Objective: To investigate predictors of SAEs during VIT and to determine whether omalizumab as an adjunct to VIT reduces SAEs and allows the continuation of VIT. Methods: We analysed the incidence and severity of SAEs during VIT in patients undergoing VIT at the University Hospital Golnik in 2005-2016 and analysed clinical (age, sex, severity of the initial reaction) and immunological (specific IgE for wasp and bee venom, recombinant IgE, basal tryptase, basophil activation test) risk factors for SAEs. Patients with VIT failure were then invited to participate in an open-label trial of omalizumab as an adjunct to VIT. Results: Systemic adverse events during VIT occurred in 10.8%. In 1.3% we had to stop VIT due to recurrent severe SAEs. The main risk factor for systemic adverse events during immunotherapy is treatment with bee venom, 23.1% patients treated with bee venom and only 1.8% treated with wasp venom had adverse events (P < 0.0001). Patients with systemic adverse events during bee venom immunotherapy had a more severe initial reaction after bee sting (P = 0.013). Patients in whom bee venom immunotherapy was discontinued due to systemic adverse events had higher basal tryptase levels (5.23 mcg/ml) compared with patients with manageable adverse events (4.29 mcg/ml) and patients without adverse events (4.35 mcg/ml) (P ⡤ 0.01). Also, patients in whom bee venom immunotherapy was discontinued due to systemic adverse events had higher basophil activation with bee venom at 0.1 mcg/ml (79.1%), compared with patients without adverse events (39.0%,) with manageable adverse events (62.6%) (P ⡤ 0.003). High basophil activation with 0.1 mcg/ml honey-bee venom was a significant and independent predictor of SAEs and VIT failure during honey-bee VIT (OR (95% CI)1.041 (1.005-1.073), P = 0.0004). Adjunct treatment with omalizumab allowed the safe and successful introduction of immunotherapy in 9/11 patients. The incidence of SAEs during VIT was significantly lower when basophil activity was below 20% when stimulated with 0.1 mcg/ml bee venom (P = 0.0004). Conclusion: We confirmed that there are predictive factors for SAEs during immunotherapy – basophil sensitivity and basal serum tryptase level. Omalizumab treatment reduces basophil sensitivity and allows the safe introduction of immunotherapy in patients with VIT failure due to SAEs. The dynamics of basophil sensitivity also predict the clinical success of adjunct omalizumab treatment

• Keywords: allergy, hymenoptera venom, anaphylaxis, immunotherapy, omalizumab, basophil, mast cell, tryptase, biomarker